Association of TLR4 Rs4986791 Polymorphism and TLR9 Haplotypes with Acute Myeloid Leukemia Susceptibility: A Case-Control Study of Adult Patients

Abstract

Toll-like receptors (TLRs) have an important role in innate immunity, and single nucleotide polymorphisms (SNPs) of TLR genes influence the risk of developing hematological malignancies. We aimed to evaluate the effect of TLR2 (rs5743708), TLR4 (rs11536889, rs4986790, rs4986791), TLR9 (rs187084, rs352140, rs5743836) on AML risk, the relation between investigated SNPs and somatic mutations, clinical features, and the overall survival of adult AML patients. All mentioned SNPs were genotyped in 511 AML cases and 503 healthy controls. DNMT3A (R882), FLT3 (D835, ITD), and NPM1 mutations’ status were investigated in AML patients. TLR4 rs4986791 was associated with an increased risk of AML under the dominant model (OR = 1.61, 95% CI: 1.001–2.59). Variant genotypes of the TLR4 rs4986790 or rs4986791 were associated with the odds of developing AML in the codominant model (OR = 3.14; 95% CI: 1.12–8.84; p = 0.032). The TLR9 rs5743836 variant genotype was associated with the NPM1 mutation (p = 0.002). The investigated SNPs were not associated with the DNMT3A, FLT3 mutations and had no significant contribution to the hazard of death after adjusting for covariates. Our findings suggest that TLR4 rs4986791 is associated with AML susceptibility. The combined variant genotypes of TLR4 rs4986790 and rs4986791 increase AML risk, the TLR9 C-G-A haplotype may represent a promising approach to predict a person’s risk for developing AML.

An updated systematic review of the association between the TLR4 polymorphism rs4986790 and cancers risk

“…There were 6 and 11 studies involving colorectal and GCs, separately. Others include acute myeloid leukemia, [ 73 ] bladder cancer, [ 68 ] breast cancer, [ 61 ] cervical cancer, [ 65 ] endometrial cancer, [ 66 ] malignant melanoma, [ 67 ] lung cancer, [ 62 ] liver cancer, [ 71 ] and chronic myeloproliferative neoplasm [ 72 ] also included in our meta-analysis. However, each of them has less than two research articles.…”

“…A wide range of tumors are involved, which encompass PC, [38][39][40][41][42][43][44] GC, [27,[45][46][47][48][49][50][51][52][53] colorectal cancer, [28,29,[54][55][56][57] non-Hodgkin's lymphoma, [58][59][60] breast cancer, [61] lung cancer, [62] and other tumors. [46,[63][64][65][66][67][68][69][70][71][72][73] The ethnic distribution of subjects is mainly Caucasian(n = 31) and Asian(n = 5). Some studies did not make a precise distinction between the ethnic groups, and we defined these as mixed ethnic groups (n = 2).…”

Genetic variation in toll-like receptor 4 gene with primary antiphospholipid syndrome susceptibility: a cohort of Egyptian patients

“…TLRs detect conserved molecules that are specific to individual microbial species, termed PAMPs, as well as endogenous molecules known as DAMPs. Activation of TLRs may trigger immune responses and inflammatory processes [28,29]. TLR4 is one the most important and well-characterized TLRs.…”

Toll-like receptor 9 (TLR9) genetic variants rs187084 and rs352140 confer protection from Behcet’s disease among Iranians

“…Besides, autoantibody production and induction of inflammatory cells are modulated through the TLR9 signaling pathway [ 14 – 16 ]. Previous studies have revealed the importance of TLR9 gene variants in the pathogenesis of autoimmune diseases such as Systemic lupus erythematosus (SLE) [ 17 – 19 ], rheumatoid arthritis (RA) [ 20 ], ankylosing spondylitis (AS) [ 21 ], acute myeloid leukemia (AML) [ 22 ], Hashimoto’s autoimmune thyroiditis [ 23 ], and Graves’ disease (GD) [ 24 ]. However, their possible association with BD has provided controversial results [ 24 ].…”